Pyridine carboxylic acid morpholides



Patented Jan. 23, 1940 V UNITED STATES PATENT OFFICE PYRIDINE CARBOXYLIC ACID MORPHOLIDES llssy, Seine, France, a

company of France No Drawing. ApplicationAugust 17, 1937, Serial No. 159,604. In France October 12, 1936 2 Claims.

At the present time there exist, among cyclic amides, various amido derivatives of nicotinic acid or, more generally, of the pyridine carboxylic acids, which derivatives have therapeutic properties.

In particular, the British Patent No. 184,625 of June 7, 1921; the U. S. Patent No. 1,403,117, filed January 10, 1922; and the U. S. Patent No. 1,617,332,. of February 15, 1927, describe dialkylamides of nicotinic acid (diethylamide, dipropylamide, diamylamide, diallylamide, methylpropylamide, ethylpropylamide, ethylbutylamide). The same patents also disclose an amide substituted by a heterocyclic group, to wit the piperidine group.

Furthermore, the French Patent No. 791,783, of January 26, 1935, describes the preparation of amido derivatives of the pyridine carboxylic acids from these acids and aliphatic or cyclic secondary amines in the presence of phosphorus pentoxide. In particular, this patent mentions the monomethylanilide of nicotinic acid, that is to say a N-phenylsubstituted aliphatic amine.

Now, we have found that the pyridine carboxylic acids can give new amido derivatives with amines such as morpholine (a complex function compound) giving results superior to those obtained up to this time with other derivatives of analogous kind.

The superiority is found in their application to therapeutics and consists in a better regularity of action and a much lower toxicity, and also an absence of convulsive effects. These advantages give a considerable value in pharmacology to the morpholic amides of the pyridine carboxylic acids.

Our invention, which is based upon the foregoing therapeutic discovery consists essentially in reacting, in the presence of suitable dehydrating reagents, and especially in the presence of phosphorus oxy-chloride, a pyridine carboxylic acid (alpha, beta or gamma) with morpholine, i. e., a secondary amine of the following formula:

CHPCH:

N o CH CQz which exhibits both a secondary amine function and an ether function.

The following examples are intended to illustrate the manufacture of morpholamides according to our invention.

It should be well understood that any variation in the process of dehydration are within the scope of the present invention, since the morpholic amides of the various pyridine carbonic acids constitute a series of new compounds.

Example I We mix, as intimately as possible, 83 parts by weight of morpholine with 110 parts by weight of nicotinic acid and we add 50 parts by weight of phosphorus oxychloride, taking care that the reaction does not become too violent but, however, raising the temperature sufficiently to enable the reaction to proceed.

We heat on a boiling water bath for about ten hours and then take up the viscous product that is obtained with 400 parts of distilled water. We saturate with potassium carbonate, and decant the insolubilized oil after which the product is dried in vacuo on a water bath. The dried oil is then taken up with benzene, filtered, and distilled in vacuo. It boils at 210 C. under a pressure of 15 mms. of mercury. The available weight is substantially the same as the weight of nicotinic acid brought into reaction.

This amide which at first has a viscous consistency, subsequently solidifies to form a solid which crystallizes normally and melts at a temperature of about 70 C. Its formula is:

un-on, CO-N I CHr-Cflz The foregoing manufacture was far from obvious, for, during treatment with phosphorus oxychloride, an alteration of the ether function of morpholine was to be expected together with regress to diethanolamine, from which said heterocyclic base was obtained.

Example II hours), we again add 9 kilograms of morpholine and the operation is continued.

After 36 hours, we again add 9 kilograms of morpholine; after 48 hours the distillation of water is found to have considerably slowed down. The process is carried on in such manner that the total duration of the operation is 72 hours.

By distillation of the solvent remaining in the apparatus we obtain 72 kilograms of morpholamide which crystallizes normally and melts at a temperature of about 70 C. This amide is purifled by rectification. If further purification is desired, we cause the rectified product to crystallize out.

The obtainment of amides from pyridine carboxylic acids and morpholine, either by causing a dehydrating agent to react with the mixture of the acid and the base, or by mere dehydration of the mixture according to the process of Example II, making use of heat and driving off of the Water by a solvent, could not, in the case of the use of morpholine, be considered as resulting necessarily from classical reactions. As a matter of fact, morpholine possesses an ether function in its molecule; this function is fairly labile and therefore capable of causing abnormal reactions so that a poor yield of amide which would have led to abandoning this kind of reaction had to be expected. In other words, the formation of morpholic amides from the various pyridine carboxylic acids could not be foreseen before experience taught that dehydration either by azeotropic method or by means of a dehydrating body gave the above mentioned results.

The foregoing examples have no limitative character as to the nature of the pyridine carboxylic acids employed or that of the dehydrating bodies employed.

What we claim is:

1. A compound of the formula CHzGH; c ON\ 0 \N/ CH2CH2 2. The morpholine amide of nicotinic acid, a

therapeutically useful compound having a melting pointof about 70 C.

GILBERT AUGUSTE LANGLOIS. AUGUSTE MARIUS DELO'ISON. 

